Abstract

We sought to determine what temporal and dose factors influence the development of tolerance to dopaminergic agents in parkinsonism. Apomorphine was administered at varying doses and durations to rats with unilateral 6-hydroxydopamine-induced nigrostriatal lesions and rotational behavior was monitored. Ten rats were studied across seven daily, intermittent treatment sessions, during which four equal boluses of apomorphine were injected at 1- to 2-hr intervals; increasing doses were used on different days. The total number of rotations were reduced by approximately 25% after repeated 0.8- and 3.2-mg/kg doses, but not after doses ranging from 0.1 to 0.4 mg/kg; neither the peak rate nor the duration of responses were altered. Nine other, untreated rats received four, 0.8-mg/kg boluses of apomorphine and did not exhibit any decrement in response. An 8-hr constant treatment (0.2-mg/kg boluses every 10 min) resulted in a 70% reduction in rotational response; plasma levels remained stable in five unlesioned rats who underwent a similar constant treatment. These results suggest that tolerance to dopaminergic stimulation is more apt to develop with constant than with intermittent treatment and that tolerance may require previous drug exposure in order to occur. Optimal treatment of patients with severe parkinsonism may require periods without dopaminergic effect in order to maintain drug response.